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We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets.

Original publication

DOI

10.1002/ana.24349

Type

Journal article

Journal

Ann Neurol

Publication Date

03/2015

Volume

77

Pages

547 - 552

Keywords

Aged, Alzheimer Disease, Amnesia, Atrophy, Cognitive Dysfunction, Disease Progression, Exome, Hippocampus, Humans, Male, Mutation, Missense, Protective Factors, Repressor Proteins, Sequence Analysis, DNA